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WO2009034029A2 - Nouveaux composés - Google Patents

Nouveaux composés Download PDF

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Publication number
WO2009034029A2
WO2009034029A2 PCT/EP2008/061771 EP2008061771W WO2009034029A2 WO 2009034029 A2 WO2009034029 A2 WO 2009034029A2 EP 2008061771 W EP2008061771 W EP 2008061771W WO 2009034029 A2 WO2009034029 A2 WO 2009034029A2
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WO
WIPO (PCT)
Prior art keywords
alkyl
group
substituted
fluorine atoms
substituents
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PCT/EP2008/061771
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German (de)
English (en)
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WO2009034029A3 (fr
Inventor
Dirk Gottschling
Georg Dahmann
Henri Doods
Alexander Dreyer
Annekatrin Heimann
Stephan Georg Mueller
Klaus Rudolf
Gerhard Schaenzle
Dirk Stenkamp
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Boehringer Ingelheim International Gmbh
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Publication of WO2009034029A2 publication Critical patent/WO2009034029A2/fr
Publication of WO2009034029A3 publication Critical patent/WO2009034029A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Heterocycle which is substituted on a nitrogen atom with a radical R 3 - 3 - 1 - 1 and on a carbon atom with one or two radicals R 3 - 3 - 1 - 3 , or (f) a heteroaryl group attached to a carbon atom a radical R 3 - 3 - 1 - substituted 3, (g) aryl-Ci- 3 alkyl-NH-, aryl-C 1-3 alkyl-N (C 1-3 alkyl) -,
  • radical R 322 optionally in addition to a nitrogen atom by a radical R 322 may be substituted and
  • a fourth embodiment of the present invention resides in the compounds of the above-mentioned conventional formulators II, IIn which are AA, XX ,, RR 22 and RR 33 'as defined above in the first, second or third embodiment and
  • Substituents R 8 may be the same or different,
  • R 1 is a group of the general formulas
  • C (R 7 1) C (R 7 - 2) or C (R 7 / I) 2 -N ( R 7 2 ) in each case a radical R 7 1 together with an adjacent radical R 7 2 and the atoms to which these radicals are bonded, also a group selected from cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl,
  • R 6 - 3 (a) H, halogen, C 1-6 alkyl, C 3 - 6 cycloalkyl,
  • R 7 - 3 (a) halogen, Ci -6 -alkyl, C 3-6 cycloalkyl,
  • Ci_3-alkyl group in which each methylene group is substituted by up to two fluorine atoms and each methyl group by up to three fluorine atoms,
  • R 9 and R 10 together may also form a ring selected from among
  • a sixth embodiment of the present invention consists in the compounds of the above general formula I in which A, X, R 2 and R 3 are as defined above in the first, second or third embodiment and
  • R 1 is a group of the general formulas
  • Ci -3 alkyl a Ci -3 alkyl, or Ci -3 alkyl-O-group wherein each methylene group with up to two fluorine atoms and each methyl group with up to three fluorine atoms is substituted,
  • Ci -3 alkyl group wherein each methylene group of up to two fluorine atoms and each methyl group with up to three fluorine atoms is substituted
  • R 8 - 1 is halogen, HO- or d -6- alkyl-O-,
  • R 9 is (a) H
  • R 3 is a group of general formula IV
  • R 3 - 1 (a) H, F, Cl, Br, -NH2, d-NH- -3 alkyl, (Ci -3 alkyl) 2 N-, H 3 CC (O) -NH- H 3 CS (O) 2 -N (Ci -3 alkyl), -CN, -OH,
  • R 3 - 3 - 1 - 2 (a) H, Ci- 4 alkyl, C 3 - 6 cycloalkyl, or (b) aryl-d- 3 alkylene,
  • R 32 and R 33 together with the carbon atoms to which they are attached form a monounsaturated 5-membered or mono- or diunsaturated 6-membered heterocycle, an aryl or heteroaryl group, wherein
  • heterocycles may contain a carbonyl, thiocarbonyl, sulfonyl or an optionally substituted by an R 32 1 substituted lmino group adjacent to a nitrogen atom, and
  • radical R 322 optionally in addition to a nitrogen atom by a radical R 322 may be substituted and
  • radical R '3.2.3 may be substituted, or
  • Another embodiment of the present invention resides in the compounds of the above general formula I in which A, X, R 1 and R 2 are as defined above under the first, second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiment are and
  • R 3 is a group selected from
  • a twelfth embodiment of the present invention is the compounds of the above general formula I in which A, X, R 1 and R 2 are as defined above in the first, second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiment are and
  • R 3 - 1 (a) H, F, Cl, Br, -NH 2 , d -3 -alkyl-NH-, H 3 CC (O) -NH-, -CN, -OH,
  • a thirteenth embodiment of the present invention is the compounds of the above general formula I wherein A, X, R 1 and R 2 are as defined above in the first, second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiment are and a group selected from
  • R 3 - 2 - 3 - 1 (a) H, (b) CN, OH 1 -O-Ci -3 -alkyl 1 CF 3 or
  • R 3 - 3 - 1 (a) R 3 - 3 - 1 - 1 R 33 1 2 N- or
  • R 3 - 4 H means
  • a sixteenth embodiment of the present invention consists in the compounds of the above general formula I in which A, X, R 1 and R 2 are as are defined above under the first, second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiment and
  • R 3 is a group selected from
  • the atom of the substituent following the point of attachment is understood as the atom with the position number 1.
  • C 1-3 -alkyl (including those which are part of other radicals) are branched and unbranched alkyl groups having 1 to 3 carbon atoms
  • C 1-4 -alkyl are branched and unbranched alkyl groups having 1 to 4 carbon atoms
  • Ci- 6 alkyl are understood to mean branched and unbranched alkyl groups having 1 to 6 carbon atoms.
  • Examples include: methyl, ethyl, n-propyl, / so-propyl, n-butyl, / so-butyl, sec-butyl, te / f-butyl, pentyl, neopentyl or n-hexyl.
  • the abbreviations Me, Et, n-Pr, / -Pr, n-Bu, / -Bu, t-Bu, etc. are also used for the abovementioned groups.
  • the definitions of propyl and butyl include all conceivable isomeric forms of the respective radicals.
  • propyl includes n-propyl and / so-propyl
  • butyl includes / so-butyl, sec-butyl and te / f-butyl, etc.
  • d- 6 -alkylene (including those which are part of other groups) are branched and unbranched alkylene groups with 1 to 6 carbon atoms and by the term are "C 1-3 alkylene” are meant branched and unbranched alkylene groups with 1 to 3
  • propylene encompasses all conceivable isomeric forms of the respective radicals of the same carbon number.
  • propyl also includes 1-methylethylene and butylene includes 1-methylpropylene, 1, 1-dimethylethylene, 1, 2-dimethylethylene.
  • C 0 alkylene means a bond.
  • C 2 - 6 -alkylene (including those which are part of other radicals) are branched and unbranched alkylene groups having 2 to 6 carbon atoms and the term "C 2 - 4 -alkylene” branched and unbranched alkylene groups having 2 to 4
  • Understood carbon atoms examples include: ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1, 1-dimethylethylene, 1, 2-dimethylethylene, pentylene, 1, 1-dimethylpropylene, 2,2, -dimethylpropylene, 1, 2 Dimethylpropylene, 1, 3-dimethylpropylene or hexylene.
  • propylene, butylene, pentylene and hexylene include all conceivable isomeric forms of the respective radicals of the same carbon number.
  • propylene also includes 1-methylethylene and butylene includes 1-methylpropylene, 1, 1-dimethylethylene, 1, 2-dimethylethylene.
  • Cs- ⁇ -cycloalkyl (including those which are part of other radicals) are cyclic alkyl groups having 3 to 6 carbon atoms and the term "Cs-e-cycloalkyl” is understood to mean cyclic alkyl groups having 5 to 6 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the cyclic alkyl groups may be substituted with one or more groups selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluoro, chloro, bromo and iodo.
  • C 3-6 -cycloalkenyl means cyclic alkylene groups having 3 to 6 carbon atoms which contain an unsaturated bond. Examples include: cyclopentenyl or cyclohexenyl. Unless otherwise stated, the cyclic alkylene groups may be substituted with one or more groups selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
  • heterocyclyl or “heterocycle”, unless otherwise specified in the definitions, means stable 5-, 6- or 7-membered monocyclic or 8-, 9-, 10- or 11-membered bicyclic heterocyclic ring systems which in at least one ring form no aromatic ring system and in addition to carbon atoms can carry one to four heteroatoms, which are selected from the group consisting of nitrogen, oxygen and sulfur. Both nitrogen atoms and sulfur atoms can optionally be oxidized and nitrogen atoms can be quaternized.
  • the heterocyclic ring may contain one or two carbonyl, thiocarbonyl or cyanimino groups adjacent to a nitrogen atom.
  • the above heterocycles may be linked via a carbon atom or via a nitrogen atom with the remainder of the molecule.
  • heterocycles may be substituted by one or more radicals selected from the group consisting of: (a) OH, NO 2 , CN, OCF 3 , OCHF 2 , OCH 2 F, NH 2 ,
  • Examples include, but are not limited to, azetidine, oxetane, thietane, thietandioxide, tetrahydrofuran, dihydrofuran, dioxalane, imidazolidine, imidazoline, imidazolidinone, dihydroimidazolone, oxazoline, oxazolidine, oxazolidinone, pyrrolidines, dihydropyrazole, pyrrolidine, pyrroline , Morpholine, tetrahydropyridine, dihydropyran, tetrahydropyran, dioxane, piperazine, piperidine, piperazinone, piperidinone, pyran, thiomorpholine-S-oxide, thiomorpholine-S-dioxide, thiomorpholine, dihydrooxazine, morpholinedione, morpholinethione, perhydrothiazine dioxide,
  • heteroaryl is understood as meaning stable five- or six-membered heterocyclic aromatics or 8- to 10-membered bicyclic heteroaryl rings which may contain one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen in each ring and additionally contain as many conjugated double bonds that an aromatic system is formed.
  • heterocyclic aromatic compounds are mentioned, but are not intended to be be limited:
  • Oxadiazole triazole, tetrazole, furazane, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine,
  • heteroaryls mentioned above may be substituted by one or more radicals selected from the group consisting of: (a) OH, NO 2 , CN, OCF 3 , OCHF 2 , OCH 2 F, NH 2 ,
  • d- 6 alkyl preferably Ci -3 alkyl, more preferably ethyl, methyl, isopropyl or te / f-butyl,
  • Bicyclic heteroaryl rings may preferably be substituted in the phenyl radical.
  • halogen is understood as meaning fluorine, chlorine, bromine or iodine atoms.
  • the application also includes the individual diastereomeric antipode pairs or mixtures thereof, which are present when more than one chirality element is present in the compounds of general formula I, as well as the individual optically active enantiomers which make up the racemates mentioned.
  • the invention further provides a process for the preparation of the compounds of general formula I, wherein the substituents have the abovementioned meaning.
  • the order of carrying out the reaction schemes can be varied to simplify the reactions or to prevent unwanted by-products.
  • the following examples are named to illustrate the invention.
  • the examples are intended to illustrate the invention and are not intended to limit the invention in any way.
  • the final product can be further derivatized, eg by manipulation of the substituents. These manipulations may be those well known to those skilled in the art such as, but not limited to, oxidation, reduction, alkylation, acylation, and hydrolysis.
  • the compounds of this invention may be prepared according to the illustrated schemes and specific examples or corresponding modifications thereof, using known and / or available starting materials, reagents and conventional synthetic methods. Of these reactions, it is also possible to use modifications which are known to a person skilled in the art but are not described in detail here.
  • a compound of general formula I in which A, R 1 , R 2 and R 3 are as defined above and X is a linker of formula (He) can be prepared by coupling an amine of general formula (1-1) in which A, R 1 , R 2 , R 3 , R 4 and R 5 are defined as mentioned above, with a carboxylic acid of the general formula (1-2) in which R 3 is defined as mentioned above with the addition of common peptide coupling reagents and a base in an inert solvent (see, for example, Houben-Weyl, Methods of Organic Chemistry, Vol.
  • the activation of the carboxyl group can alternatively also be carried out via the acid anhydride or acid chloride by methods which are known to the person skilled in the art.
  • auxiliary bases for the coupling of the activated carboxyl function with a suitable amine for example triethylamine, ethyldiisopropylamine, morpholine or other tertiary amine bases can be used.
  • the Cbz protecting group may be removed by standard methods known to those skilled in the art.
  • the reaction is generally carried out in inert solvents, in the presence of a catalyst, preferably palladium on carbon, at room temperature in a hydrogen atmosphere under elevated pressure.
  • a catalyst preferably palladium on carbon
  • the activation of the carboxyl group takes place via a corresponding acid anhydride or acid chloride.
  • the reaction is generally carried out in inert solvents in the presence of a base, preferably in a temperature range from room temperature to reflux of the solvent at atmospheric pressure.
  • the reaction starts with an aromatic compound of the general formula (4-1) in which R 3 is defined as mentioned above, which under Friedel-Crafts conditions with a Succinic anhydride derivative of the general formula (4-2) in which R 4 and R 5 are defined as mentioned above, and a Lewis acid is reacted in an inert solvent.
  • the reaction is preferably carried out in a temperature range from 0 ° C. to the reflux of the solvent under atmospheric pressure.
  • the compounds of the general formula (7-3) in which R 1 and R 2 are defined as mentioned above can be hydrogenated with a catalyst and hydrogen in a temperature range from room temperature to reflux of the solvent at elevated pressure.
  • Particularly preferred is the use of Raney nickel in ethanolic ammonia in a 3 bar hydrogen atmosphere at 50 0 C.
  • Ethyl- (3-dimethylamino-propyl) -carbodiimide O- (1H-benzotriazol-1-yl) -N, NN, N-tetramethyl-uronium-hexa-fluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1 H-Benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP).
  • HBTU N-tetramethyl-uronium-hexa-fluorophosphate
  • TBTU tetrafluoroborate
  • BOP 1 H-Benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate
  • nitroaryl derivatives of the general formula (8-1) in which R 6 is as hereinbefore defined are with chlorophenoxyacetonitrile under Zuzz- would take a base in an inert solvent in a temperature range of -20 0 C to reflux of the solvent implemented. Most particularly preferred are reactions in DMF, potassium-te / f-butoxide as base at a temperature of -10 0 C under atmospheric pressure.
  • the reduction of a nitrile of the general formula (8-2) in which R 6 is defined as mentioned above gives a corresponding amine of the general formula (8-3) in which R 6 is defined as mentioned above.
  • Such reductions are known to the person skilled in the art.
  • Particularly preferred is the use of 1 M borane in THF.
  • the amino functionality can be alkylated by methods known to those skilled in the art. Particularly preferred are reductive aminations.
  • An amine of the general formula (8-3) in which R 6 is defined as mentioned above reacts with a ketone of the general formula (8-8) in which R 2 is defined as mentioned above, in the presence of an acid and a reducing agent.
  • the reaction is carried out in inert solvents, such as chlorinated hydrocarbons or ethers.
  • Preferred solvents are dichloromethane, 1, 2-dichloroethane, diethyl ether, THF or mixtures thereof.
  • Suitable acids are mineral acids such as acetic acid or hydrochloric acid, or organic acids such as p-toluenesulfone acid.
  • novel compounds of general formula I according to the invention may contain one or more chiral centers. For example, if there are two chiral centers, then the compounds can be in the form of two diastereomeric antipode pairs.
  • the invention includes the individual isomers as well as their mixtures. The separation of the respective diastereomers succeeds on the basis of their different physicochemical properties, for example by fractional crystallization from suitable solvents, by high-pressure liquid or column chromatography using chiral or preferably achiral stationary phases.
  • the racemate of a compound of the general formula I is reacted with one of the abovementioned optically active acids or bases in an equimolar amount in a solvent and the resulting crystalline, diastereomeric, optically active salts are separated by utilizing their different solubilities.
  • This reaction can be carried out in any kind of solvents as long as they have a sufficient difference in the solubility of the salts.
  • methanol, ethanol or mixtures thereof, for example in the volume ratio 50:50, are used.
  • each of the optically active salts is dissolved in water, carefully neutralized with a base such as sodium carbonate or potassium carbonate, or with a suitable acid, for example with dilute hydrochloric acid or aqueous methanesulfonic acid, thereby giving the corresponding free compound in the (+) - or ( -) - Form received.
  • a base such as sodium carbonate or potassium carbonate
  • a suitable acid for example with dilute hydrochloric acid or aqueous methanesulfonic acid
  • SK-N-MC cells are cultured in "Dulbecco's modified Eagle Medium”. The medium of confluent cultures is removed. The cells are washed twice with PBS buffer (Gibco 041-04190 M), removed by addition of PBS buffer, mixed with 0.02% EDTA, and isolated by centrifugation. After resuspension in 20 ml Balanced Salts Solution [BSS (in mM): NaCl 120, KCl 5.4, NaHCO 3 16.2, MgSO 4 0.8, NaHPO 4 1.0, CaCl 2 1.8, D-glucose 5.5, HEPES 30, pH 7.40]. The cells are centrifuged twice at 100 xg and resuspended in BSS.
  • BSS Balanced Salts Solution
  • the cells are homogenized using an Ultra-Turrax and centrifuged for 10 minutes at 3000 xg. The supernatant is discarded and the pellet in Tris buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCl 2 , 1 mM EDTA, pH 7.40), supplemented with 1% bovine serum albumin and 0.1%.
  • the cAMP contents of the samples are determined by means of radioimmunoassay (Amersham) and the pA 2 values of antagonistic substances are determined graphically.
  • the compounds of the invention show in the described in v / fr-o test model CGRP antagonistic properties in a dose range between 10 "12 to 10 " 5 M.
  • the compounds according to the invention and their salts with physiologically tolerated acids are thus suitable for the acute and prophylactic treatment of headaches, in particular migraine, cluster headache and tension-type headaches.
  • the compounds according to the invention also have a positive influence on the following diseases: non-insulin-dependent diabetes mellitus ("NIDDM”), cardiovascular diseases, morphine tolerance, Clostridium toxin-induced diarrheal diseases, skin disorders, especially thermal and radiation-related skin damage including sunburn, skin, prurigo, pruriginous toxidermias as well as severe itching, inflammatory diseases, eg inflammatory joint diseases (osteoarthritis, rheumatoid arthritis, neurogenic arthritis), generalized soft tissue rheumatism (fibromyalgia), neurogenic inflammations of the oral mucosa, inflammatory lung diseases, allergic rhinitis, asthma, COPD, diseases associated with excessive vasodilation and consequent reduced tissue perfusion, eg, shock and sep
  • NIDDM non-insul
  • the compounds according to the invention have a soothing effect on pain conditions in general.
  • the symptoms of menopausal, caused by vasodilation and increased blood flow hot flushes of estrogen-deficient women and hormone-treated prostate cancer patients and castrates is influenced by the CGRP antagonists of the present application preventively and acutely therapeutically favored, this therapy approach is characterized by hormone substitution by side effect poverty.
  • the compounds according to the invention are preferably suitable for the acute and prophylactic treatment of migraine and cluster headache, for the treatment of irritable bowel syndrome (IBS) and for the preventive and acute therapeutic treatment of hot flushes of estrogen-deficient women.
  • IBS irritable bowel syndrome
  • the dosage required to achieve a corresponding effect is expediently by intravenous or subcutaneous administration 0.0001 to 3 mg / kg body weight, preferably 0.01 to 1 mg / kg body weight, and by oral, nasal or inhalative administration 0.01 to 10 mg / kg body weight, preferably 0.1 to 10 mg / kg body weight, one to three times daily.
  • CGRP antagonists or / and CGRP-release inhibitors are in addition to a conventional hormone substitution, it is recommended to reduce the dosages given above, the dosage then being 1/5 of the lower limits specified above up to 1/1 of the above may be upper limits.
  • Another object of the invention is the use of the compounds according to the invention as valuable aids for the production and purification (affinity chromatography).
  • radioactive labeling for example by tritiation of suitable precursors, for example by catalytic hydrogenation with trithium or replacement of halogen atoms by tritium, in RIA and ELISA assays and as diagnostic or analytical tools in neurotransmitter research.
  • agents include antiemetics, prokinetics, neuroleptics, antidepressants, neurokinin antagonists, anticonvulsants, histamine H1 receptor antagonists, ⁇ -blockers, ⁇ -agonists and ⁇ -antagonists, ergot alkaloids, weak analgesics, nonsteroidal anti-inflammatory drugs, corticosteroids, calcium Antagonists, 5-HT 1B / i D agonists or other antimigraine agents, together with one or more inert customary carriers and / or diluents, for example corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, Water / ethanol, water / -
  • the non-steroidal anti-inflammatory drugs aceclofenac, acemetacin, acetylsalicylic acid, acetaminophen (paracetamol), azathioprine, diclofenac, diflunisal, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, leflunomide, lornoxicam, mefenamic acid are thus used as further active substances , Naproxen, phenylbutazone, piroxicam, sulfasalazine, zomepirac or their pharmaceutically acceptable salts, as well as meloxicam and other selective COX2 inhibitors, such as rofecoxib, valdecoxib, parecoxib, etoricoxib and celecoxib, as well as substances which inhibit earlier or later steps in prostaglandin. Inhibit synthesis
  • CGRP antagonists with vanilloid receptor antagonists e.g. VR-1 antagonists, glutamate receptor antagonists, e.g. mGlu5 receptor antagonists, mGlui receptor antagonists, iGlu5 receptor antagonists, AM-PA receptor antagonists, purine receptor blockers, e.g. P2X3 antagonists, NO synthase inhibitors, e.g. iNOS inhibitors, calcium channel blockers, e.g. PQ-type blockers, N-type blockers, potassium channel openers, e.g. KCNQ channel openers, sodium channel blockers, e.g. PN3 channel blockers, NMDA receptor antagonists, acid-sensing ion channel antagonists, e.g.
  • bradykinin receptor antagonists such as e.g. B1 receptor antagonists, cannabinoid receptor agonists, e.g. CB2 agonists, CB1 agonists, somatostatin receptor agonists, e.g. sst2 receptor agonists are given.
  • the dose for these active substances is expediently 1/5 of the usually recommended lowest dosage up to 1/1 of the normally recommended dosage, so for example 20 to 100 mg sumatriptan.
  • the compounds according to the invention may be administered either alone or optionally in combination with other active substances for the treatment of migraine intravenously, subcutaneously, intramuscularly, intraarticularly, intrarectally, intranasally, by inhalation, topically, transdermally or orally, in particular aerosol formulations being suitable for inhalation.
  • the combinations may be administered either simultaneously or sequentially.
  • Suitable application forms are, for example, tablets, capsules, solutions, juices, emulsions or inhalable powders or aerosols.
  • the proportion of the pharmaceutically active compound (s) in each case in the range of 0.1 to 90 wt .-%, preferably 0.5 to 50 wt .-% of the total composition, ie in amounts which are sufficient to reach the above-mentioned dosage range.
  • Oral administration may be in the form of a tablet, as a powder, as a powder in a capsule (e.g., hard gelatin capsule), as a solution or suspension.
  • the active substance combination can be carried out as a powder, as an aqueous or aqueous-ethanolic solution or by means of a propellant gas formulation.
  • compositions are preferably characterized by the content of one or more compounds of the formula I according to the above preferred embodiments.
  • Corresponding tablets can be prepared, for example, by mixing the active substance (s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents for achieving the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • the tablets can also consist of several layers.
  • Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetening agent, such as saccharin, cyclamate, glycerol or sugar, and a taste-improving agent, for example flavorings, such as vanillin or orange extract.
  • a sweetening agent such as saccharin, cyclamate, glycerol or sugar
  • a taste-improving agent for example flavorings, such as vanillin or orange extract.
  • the capsules containing one or more active ingredients or combinations of active substances can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules.
  • suitable suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.
  • Adjuvants may include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g., petroleum fractions), oils of vegetable origin (e.g., peanut or sesame oil), mono- or polyfunctional alcohols (e.g., ethanol or glycerin), carriers such as e.g.
  • pharmaceutically acceptable organic solvents such as paraffins (e.g., petroleum fractions), oils of vegetable origin (e.g., peanut or sesame oil), mono- or polyfunctional alcohols (e.g., ethanol or glycerin), carriers such as e.g.
  • ground natural minerals eg kaolins, clays, talc, chalk
  • ground synthetic minerals eg fumed silica and silicates
  • sugars eg pipe, milk and dextrose
  • emulsifiers eg lignin, liquors, methylcellulose, starch and polyvinylpyrrolidone
  • lubricants eg Magnesium stearate, talc, stearic acid and sodium lauryl sulfate.
  • propellant-free inhalable solutions also includes concentrates or sterile, ready-to-use inhalable solutions.
  • the administration forms which can be used in the context of the present invention will be described in detail in the following part of the description.
  • the ratios indicated for the flow agents relate to volume units of the respective solvents.
  • the indicated volume units at NH 3 refer to a concentrated solution of NH 3 in water.
  • the acid, base and salt solutions used in the workup of the reaction solutions are aqueous systems of the indicated concentrations.
  • silica gel from Millipore MATREX TM, 35-70 ⁇ m is used.
  • HPLC data are collected under the parameters listed below and using the listed columns:
  • solvent A water (with 0.1% formic acid)
  • Solvent B acetonitrile (with 0.1% NH 4 OH)
  • Solvent A water (with 0.1% trifluoroacetic acid)
  • Solvent B acetonitrile (with 0.1% trifluoroacetic acid)
  • Preparative HPLC purifications generally use the same gradients used in the collection of analytical HPLC data.
  • the collection of products is mass-controlled, the product-containing fractions are combined and freeze-dried.
  • Step 3 (1-Benzyl-piperidin-4-yl) - [2- (5-methoxy-2-nitrophenyl) -ethyl-1-amine
  • Step 1 ⁇ 2- [4- (7-Methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidin-1-yl-1-2-oxo-ethyl) - -carbamic
  • Step 2 3- [1- (2-Aminoacetyl) -piperidine-4-vH-7-methoxy-1,3-A5-tetrahydro-1,3-benzodiazepin-2-one
  • Step 1 ⁇ 2-Oxo-2- [4- (2-oxo-1, 2 A5-tetrahydro-1, 3-benzodiazepin-3-yl) -piperidine-1 ⁇ yli-ethvD-carbamic acid benzyl ester
  • Step 1 ⁇ 2-Oxo-2-r4- (2-oxo-2,3-dihydroimidazor4,5-olpyridin-1-yl) -piperidin-1-yl-ethyl) -carbamic acid benzyl ester
  • Step 2 1 - [1- (2-Amino-acetyl) -piperidin-4-yl-1, 3-dihydroimidazo [4,5- ⁇ 1-pyridin-2-one
  • Methanol was hydrogenated for 1 h at RT in a hydrogen atmosphere of 3 bar.
  • Step 1 [4- (7-methoxy-2-oxo-1, 2, 4,5-tetrahydro-1, 3-benzodiazepin-3-yl) -piperidine-1 ⁇ yli-acetonitrile
  • Step 1 4- (Cyclopropanecarbonyl-amino) -3-methyl-benzoic acid methyl ester
  • Step 4 2-Cyclopropyl-7-methyl-1 / - / - benzimidazole-5-carboxylic acid methyl ester
  • Step 5 2-Cyclopropyl-7-methyl-1 / - / - benzimidazole-5-carboxylic acid
  • Step 2 4-Methyl-2-oxo-2,3-dihydro-benzoxazole-6-carboxylic acid
  • Step 1 7-Methyl-2-oxo-2,3-dihydro-1 / - / - benzimidazole-5-carboxylic acid methyl ester
  • Step 2 7-Methyl-2-oxo-2,3-dihydro-1 / - / - benzimidazole-5-carboxylic acid
  • Step 1 7-Methyl-1 / - / - benzotriazole-5-carboxylic acid methyl ester
  • Step 1 7-Methyl-3 / - / - benzimidazole-5-carboxylic acid methyl ester
  • Step 2 7-Methyl-3 / - / - benzimidazole-5-carboxylic acid
  • Step 1 3-Chloro-5- (2-ethyl-piperidine-1-carbonyl) -benzoic acid methyl ester
  • Step 1 4-Methyl-2-oxo-2,3-dihydro-benzooxazole-6-carboxylic acid benzyl ester
  • Step 2 Benzyl 3,4-dimethyl-2-oxo-2,3-dihydro-benzooxazole-6-carboxylate
  • Step 2 4- (7-Bromo-2-cavanamino-1H-benzimidazol-5-yl) -4-oxo-butyric acid methyl ester and 4- (7-bromo-2-ureido-1 / - / - benzimidazole-5- yl) -4-oxo-butyric acid methyl ester
  • Step 3 4- (7-Bromo-2-covanoamino-1 / - / - benzimidazol-5-yl) -4-oxo-butyric acid and 4- (7-bromo-2-ureido-1 / - / - benzimidazole-5 yl) -4-oxo-butyric acid
  • Step 1 4- (3-Acetylamino-2,4-dimethylphenyl) -4-oxo-butyric acid
  • Step 2 4- (3-Amino-2,4-dimethylphenyl) -4-oxo-butyric acid hydrochloride
  • Step 1 4- (4-Methyl-2-oxo-2,3-dihydro-benzooxazol-6-yl) -4-oxo-butyric acid methyl ester
  • Step 1 4- (7-bromo-2-oxo-1, 2, 4,5-tetrahydro-1, 3-benzodiazepin-3-yl) -piperidine-1 ⁇ carboxylic acid fe / f-butyl ester
  • the batch was cooled, filtered through a frit and concentrated by rotary evaporation.
  • the residue was stirred in 10 ml of DCM with the addition of 2.0 ml of trifluoroacetic acid at RT overnight.
  • the mixture was i.vac. concentrated and the remaining residue stirred with diethyl ether.
  • the precipitated as a solid product was filtered off with suction and i.vac. dried.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux antagonistes du CGRP représentés par la formule générale (I), dans laquelle A, X, R1, R2 et R3 sont tels que définis dans la description, leurs tautomères, leurs isomères, leurs diastéréoisomères leurs énantiomères, leurs hydrates, leurs mélanges, et leurs sels, ainsi que les hydrates des sels, en particulier, leurs sels physiologiquement acceptables comprenant des acides ou des bases inorganiques ou organiques, des médicaments contenant ces composés, leur utilisation et leur procédé de production.
PCT/EP2008/061771 2007-09-07 2008-09-05 Nouveaux composés WO2009034029A2 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8450327B2 (en) 2007-10-18 2013-05-28 Boehringer Ingelheim International Gmbh CGRP antagonists
US8629137B2 (en) 2007-10-18 2014-01-14 Boehringer Ingelheim International Gmbh CGRP antagonists
US8829006B2 (en) 2007-11-22 2014-09-09 Boehringer Ingelheim International Gmbh Compounds
JP2016531942A (ja) * 2013-09-26 2016-10-13 シーエイチディーアイ ファウンデーション，インコーポレーテッド キヌレニン−３−モノオキシゲナーゼ阻害薬、医薬組成物、及びこれらの使用方法
EP3130583A1 (fr) * 2012-04-05 2017-02-15 CHDI Foundation, Inc. Inhibiteurs de kynurenine-3-monooxygenase, compositions pharmaceutiques et leurs procédés d'utilisation
US9884853B2 (en) * 2013-09-26 2018-02-06 Chdi Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
CN112624979A (zh) * 2019-10-09 2021-04-09 浙江瑞博制药有限公司 一种苯并咪唑化合物的制备方法
US11400081B2 (en) 2017-05-17 2022-08-02 The University Of Sheffield Compounds

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK131147B (da) * 1969-10-27 1975-06-02 Sumitomo Chemical Co Fremgangsmåde til fremstilling af butyrophenonderivater eller syreadditionssalte deraf.
PH17194A (en) * 1980-03-06 1984-06-19 Otsuka Pharma Co Ltd Novel carbostyril derivatives,and pharmaceutical composition containing the same
DE19952147A1 (de) * 1999-10-29 2001-05-03 Boehringer Ingelheim Pharma Neue Cyclopropane, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
DE19952146A1 (de) * 1999-10-29 2001-06-07 Boehringer Ingelheim Pharma Arylalkane, Arylalkene und Aryl-azaalkane, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8450327B2 (en) 2007-10-18 2013-05-28 Boehringer Ingelheim International Gmbh CGRP antagonists
US8629137B2 (en) 2007-10-18 2014-01-14 Boehringer Ingelheim International Gmbh CGRP antagonists
US8829006B2 (en) 2007-11-22 2014-09-09 Boehringer Ingelheim International Gmbh Compounds
JP2018108997A (ja) * 2012-04-05 2018-07-12 シーエイチディーアイ ファウンデーション，インコーポレーテッド キヌレニン−３−モノオキシゲナーゼインヒビターおよびその医薬組成物ならびにこれらの使用方法
EP3130583A1 (fr) * 2012-04-05 2017-02-15 CHDI Foundation, Inc. Inhibiteurs de kynurenine-3-monooxygenase, compositions pharmaceutiques et leurs procédés d'utilisation
US9822058B2 (en) 2012-04-05 2017-11-21 Chdi Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US10442782B2 (en) * 2012-04-05 2019-10-15 Chdi Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
EP3049389A4 (fr) * 2013-09-26 2017-04-19 CHDI Foundation, Inc. Inhibiteurs de kynurénine-3-monooxygénase, compositions pharmaceutiques et procédés d'utilisation de ceux-ci
US9884853B2 (en) * 2013-09-26 2018-02-06 Chdi Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US9938252B2 (en) 2013-09-26 2018-04-10 Chdi Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
JP2016531942A (ja) * 2013-09-26 2016-10-13 シーエイチディーアイ ファウンデーション，インコーポレーテッド キヌレニン−３−モノオキシゲナーゼ阻害薬、医薬組成物、及びこれらの使用方法
US10428054B2 (en) 2013-09-26 2019-10-01 Chdi Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US10501433B2 (en) 2013-09-26 2019-12-10 Chdi Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US11400081B2 (en) 2017-05-17 2022-08-02 The University Of Sheffield Compounds
CN112624979A (zh) * 2019-10-09 2021-04-09 浙江瑞博制药有限公司 一种苯并咪唑化合物的制备方法

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